Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway

Wu, Jinjun; Zhu, Yuanfeng; Guo, Zhenzhen; Lou, Yanmei; He, Shugui; Guan, Yang; Zhu, Lijun; Liu, Zhongqiu; Lu, Linlin; Liu, Liang

doi:10.1016/j.phymed.2017.12.007

Cited by 26 publications

(12 citation statements)

References 32 publications

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“…Collectively, these results indicate that PE treatment plays an important role in breast cancer development and prevention by suppressing NF-κB-mediated inflammatory pathways through Nrf2-dependent and independent mechanisms as indicated in Table 1. Numerous other phytochemicals present in plants and medical herbs can act with similar mechanisms against breast cancer 88–91. Therefore, the development of highly specific activators of Nrf2 can significantly improve the anti-inflammatory functions in oxidative stress-related diseases, especially in breast cancer 92.…”

Section: Role Of the Nrf2–are Pathway In Inflammatory Signaling Involmentioning

confidence: 99%

<p>Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms</p>

Giudice

Barbieri

Bimonte

et al. 2019

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Breast cancer is the most common malignancy among women worldwide. Various studies indicate that prolonged exposure to elevated levels of estrogens is associated with development of breast cancer. Both estrogen receptor-dependent and independent mechanisms can contribute to the carcinogenic effects of estrogens. Among them, the oxidative metabolism of estrogens plays a key role in the initiation of estradiol-induced breast cancer by generation of reactive estrogen quinones as well as the associated formation of oxygen free radicals. These genotoxic metabolites can react with DNA to form unstable DNA adducts which generate mutations leading to the initiation of breast cancer. A variety of endogenous and exogenous factors can alter estrogen homeostasis and generate genotoxic metabolites. The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes (CYP19, CYP1B1) but also through the induction of various cytoprotective enzymes (eg, SOD3, NQO1, glutathione S-transferases, OGG-1, catechol- O -methyltransferases, CYP1B1A, etc.) that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.

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Section: Role Of the Nrf2–are Pathway In Inflammatory Signaling Involmentioning

confidence: 99%

<p>Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms</p>

Giudice

Barbieri

Bimonte

et al. 2019

OTT

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“…BCRP belongs to this family of efflux transporters responsible for drug disposition and distribution. BCRP expression is significantly associated with tumor response to chemotherapy and resistance (Faneyte et al, 2002; Wu et al, 2018). Mutations in the EGFR also confer drug resistance in non-small cell lung cancer (NSCLC) and other tumor types (Cortot and Janne, 2014), e.g., the T790M mutation, alternative pathways activation, loss of function of the EGFR-mediated apoptosis pathway (Huang and Fu, 2015).…”

Section: Introductionmentioning

confidence: 99%

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines

2019

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Parthenolide (PT) is a sesquiterpene lactone isolated from Tanacetum parthenium . In this study, PT showed varying cytotoxic effects against different solid tumor cell lines. HCT116 (p53 +/+ ) colon carcinoma cells and their parental HCT116 knockout p53 (p53 -/- ) cell lines showed a resistance degree of 2.36. On the other hand, wild-type U87.MG cells or cells transfected with a deletion-activated EGFR cDNA (U87.MGΔEGFR) exhibited slight sensitivity toward PT. Multidrug-resistant MDA-MB-231-BCRP cells were even more sensitive toward PT than sensitive MDA-MB-231-pcDNA cells with a resistance degree of 0.07 (collateral sensitivity). To the best of our knowledge, hypersensitivity (collateral sensitivity) in MDA-MB-231-BCRP cell line is reported in this study for the first time. We attempted to identify the mechanism of collateral sensitivity. Firstly, we found that PT bound to IKK preventing IκBα degradation and eventually inhibition of the nuclear factor kappa B (NF-κB) pathway. Down-regulation of hypoxia inducing factor 1-alpha (HIF-1α) in MDA-MB-231-BCRP resistant cells may be a second mechanism, since it is a target gene of NF-κB. Moreover, PT also showed epigenetic effect by inhibition of HDAC activity as shown using both molecular docking and HDAC activity assay. Based on COMPARE and hierarchical cluster analyses, we found gene expression profiles that predicted sensitivity or resistance of 47 tumor cell lines toward PT. Interestingly, pathway analyses of gene expression profiles revealed NF-κB and HIF signaling as top networks of these genes, cellular functions and canonical pathways influencing the activity of PT against tumor cells. In conclusion, PT exerted profound cytotoxic activity against various cancer cell lines mainly against BCRP-overexpressing tumor cells, suggesting PT as novel candidate for cancer treatment.

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“…Many relevant mechanisms for cytotoxic drug resistance have been described and discussed [ 1 , 6 , 7 ], among which the overexpression of the ATP-binding cassette (ABC) transporter proteins belongs to the most prominent MDR mechanisms. These membrane proteins represent one of the largest gene families in human beings and are responsible for the reduction of intracellular accumulation of many classical anticancer drugs below the effective level leading to drug resistance and treatment failure [ 8 , 9 ]. P-glycoprotein ( ABCB1/MDR1 ) is one of the most studied ABC transporters that are overexpressed in many tumor types [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation

et al. 2018

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Nimbolide is considered a promising natural product in cancer prevention and treatment. However, it is not known yet, whether the different mechanisms of multidrug resistance (MDR) influence its anticancer activity. In this study, well-known MDR mechanisms (ABCB1, ABCG2, ABCB5, TP53, EGFR) were evaluated against nimbolide. The P-glycoprotein (ABCB1/MDR1)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in ABCB1/MDR1 mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. The expression of breast cancer resistance protein (BCRP) as well as epidermal growth factor receptor (EGFR) and mutant tumor suppressor TP53 did not correlate to nimbolide’s activity. Furthermore, this paper looked for other molecular determinants that might determine tumor cellular response towards nimbolide. COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based mRNA expressions of the NCI 60 cell line panel were performed, and a set of 40 genes from different functional groups was identified. The data suggested NF-κB as master regulator of nimbolide’s activity. Interestingly, HIF1α was determined by COMPARE analysis to mediate sensitivity to nimbolide, which would be of great benefit in targeted therapy.

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Aconitum alkaloids, the major components of Aconitum species, affect expression of multidrug resistance-associated protein 2 and breast cancer resistance protein by activating the Nrf2-mediated signalling pathway

Cited by 26 publications

References 32 publications

<p>Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms</p>

<p>Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms</p>

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines

Cytotoxicity of nimbolide towards multidrug-resistant tumor cells and hypersensitivity via cellular metabolic modulation

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